Evaluation of intranasal nafamostat or camostat for SARS-CoV-2 chemoprophylaxis in Syrian golden hamsters

  1. M Neary
  2. H Box
  3. J Sharp
  4. L Tatham
  5. P Curley
  6. J Herriott
  7. E Kijak
  8. U Arshad
  9. JJ Hobson
  10. RKR Rajoli
  11. H Pertinez
  12. A Valentijn
  13. K Dhaliwal
  14. F McCaughan
  15. SP Rannard
  16. A Kipar
  17. JP Stewart
  18. A Owen

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Abstract

Successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention implementable alongside vaccination programmes. Camostat and nafamostat are serine protease inhibitors that inhibit SARS-CoV-2 viral entry in vitro but have not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and while camostat is orally available, both drugs have extremely short plasma half-lives. This study sought to determine whether intranasal dosing at 5 mg/kg twice daily was able to prevent airborne transmission of SARS-CoV-2 from infected to uninfected Syrian golden hamsters. SARS-CoV-2 viral RNA was above the limits of quantification in both saline- and camostat-treated hamsters 5 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, intranasal nafamostat-treated hamsters remained RNA negative for the full 7 days of cohabitation. Changes in body weight over the course of the experiment were supportive of a lack of clinical symptomology in nafamostat-treated but not saline- or camostat-treated animals. These data are strongly supportive of the utility of intranasally delivered nafamostat for prevention of SARS-CoV-2 infection and further studies are underway to confirm absence of pulmonary infection and pathological changes.

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    SciScore for 10.1101/2021.07.08.451654: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsField Sample Permit: All animal studies were conducted in accordance with UK Home Office Animals Scientific Procedures Act (ASPA, 1986).
    IACUC: Additionally, all studies were approved by the local University of Liverpool Animal Welfare and Ethical Review Body and performed under UK Home Office Project Licence PP4715265.
    Euthanasia Agents: In all cases, animal sacrifice was conducted via a lethal intraperitoneal injection of pentobarbitone, followed by cardiac puncture and immediate exsanguination of blood from the heart.
    Sex as a biological variableMale Syrian Golden hamsters were purchased from Janvier Labs.
    RandomizationHamsters were randomly assigned into groups of four and acclimatised for 7 days.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All statistical analysis was completed using GraphPad Prism version 8.3.0.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    However, it should be noted that hamsters are obligate nasal breathers,23 which presents a potential limitation of this species for characterising intranasally delivered chemoprophylactic interventions. The importance of this for future applicability in humans is uncertain but it should be noted. Detectable viral RNA in swab samples from day 1 through day 7 were observed in animals receiving intranasal camostat, indicating a lack of chemoprophylactic benefit against SARS-CoV-2 infection at a dose of 10mg/kg/day. Conversely, viral RNA in swabs collected from the intranasal nafamostat group remained below the LOQ throughout the period of cohabitation with infected animals. Importantly, body weight has emerged as an important clinical outcome for severity of disease in the hamster model.24 Nafamostat but not camostat was also able to prevent the infection-mediated body weight decline that was observed in both directly inoculated and saline-treated control animals. Taken collectively, these data clearly demonstrate that 5mg/kg of intranasally twice daily-administered nafamostat but not camostat is able to prevent transmission from infected animals to healthy animals while they receive the drug. Viral RNA became detectable within the throat swabs of nafamostat-treated animals on day 9, two days after discontinuation of the drug and despite infected animals being culled at the time of drug discontinuation. The current experimental design is not suitable to determine the reasons why...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2021.07.08.451654v1 on bioRxiv